Shwachman-Diamond syndrome (SDS) is a recessive disorder with exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow failure. The hematological complications include the most serious concerns for morbidity and mortality with severe infections, depression of myeloid lineages and development of leukemia. With the recent identification of SBDS, the gene that is mutated in this disorder, the proposed investigations seek to establish and understand its function and role during development, as well as determine the consequences of the loss of this gene in the most critically affected organs. The aims of the investigations build on previous work including a) molecular genetic studies that were used to identify the gene, b) the realization that the gene is highly conserved through evolution, and 3) on the development of disease models. Our current working hypotheses are that SBDS is involved in RNA metabolism or ribosome biogenesis and that SDS is due to hypomorphic alleles of SBDS with corresponding marked reduction of function. We propose to - 1) carry out genotype/phenotype correlations with respect to disease severity including occurrence of severe hematological complications and complete the characterization of the mutations in our collection of 300 families, 2) understand the consequence of loss of SBDS and development of disease in the affected organs including blood and bone marrow compartments by investigating mouse models and 3) determine the function of SBDS by pursuing localization, binding studies (protein and RNA) and detailed differential expression analysis with yeast and cell culture model systems. The elucidation of the detailed function and interactions of SBDS is essential to provide insight toward the development of rationalized therapies, including either gene or gene based therapies for SDS. The similarity of the hematological components of SDS to other congenital bone marrow failure syndromes also suggests that these studies may reveal strategies for treatments for these related diseases.